Novel thiol esters and process for preparing cephalosporin compounds using same

ABSTRACT

An 1,3,4-thiadiazole-5-thiol ester of the formula, ##STR1## wherein R is a hydrogen atom or a methyl group, a process for their preparation and a process for preparing a cephalosporin compound of the formula, ##STR2## wherein R is the same as defined above, using the above described 1,3,4-thiadiazole-5-thiol ester.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a novel thiol ester having utility as asleep-inducing agent, an antibacterial agent and an acylating agent foramines and hydrazines, particularly as active esters for preparingcephalosporin compounds, a process for their preparation and a processfor the preparation of cephalosporin compounds using the thiol esters.

2. Description of the Prior Art

An 1,3,4-thiadiazole-5-thiol ester of the formula, ##STR3## wherein R isa hydrogen atom or a methyl group, and a process for its preparationhave not been reported yet.

Further, heretofore, any method is not known for preparing acephalosporin compound of the formula, ##STR4## wherein R is a hydrogenatom or a methyl group, by one step using 7-aminocephalosporanic acid orits derivative as the starting material. In order to obtain the abovedescribed cephalosporin compound, it is necessary to employ the methodsas described in U.S. Pat. Nos. 3,278,531 and 3,516,997, Japanese PatentPublication Nos. 5150/1971 and 35751/1971 as a combination. For example,the above described cephalosporin compound may be prepared by two steps,i.e., either by firstly reacting 7-aminocephalosporanic acid with1H-tetrazole1-acetic acid and secondly reacting the7-(1H-tetrazol-1-ylacetamido)cephalosporanic acid thus obtained with an1,3,4-thiadiazole-5-thiol or by firstly reacting 7-aminocephalosporanicacid with an 1,3,4-thiadiazole-5-thiol and secondly reacting the7-amino-3-(1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acidthus obtained with 1H-tetrazole1-acetic acid. Thus, these methodsrequire two-step operation, and further a separation procedure such asan extraction with a solvent for recovering the unstable product formedin the first step and, as a result, the yield is too low for practicalpurposes.

SUMMARY OF THE INVENTION

Accordingly, the present invention in one embodiment provides an1,3,4-thiadiazole-5-thiol ester of the formula, ##STR5## wherein R is ahydrogen atom or a methyl group.

The present invention in another embodiment provides a process forpreparing the above described compound of Formula (I).

In a further embodiment, the invention provides a process for preparinga cephalosporin compound of the formula, ##STR6## wherein R is the sameas defined above, which comprises reacting 7-aminocephalosporanic acidor its derivative with the above described compound of Formula (I).

DETAILED DESCRIPTION OF THE INVENTION

The 1,3,4-thiadiazole-5-thiol esters of Formula (I) of this inventionare 1H-tetrazole-1-acetic acid 1,3,4-thiadiazol-5-ylthiol ester and1H-tetrazole-1-acetic acid 2-metyl-1,3,4-thiadiazol-5-ylthiol ester.

These compounds of Formula (I) of this invention as such are novelcompounds and useful as sleep-inducing agents and antibacterial agentsof high value.

More specifically, the compounds of Formula (I) of this invention havebeen found to exhibit an anesthetic effect, i.e., a sleep-inducingeffect according to the following experiment.

Male ddY-strain mice aged 7 or 6 weeks, each group consisting of 8animals, were given an intravenous injection of 35 mg/Kg of sodiumthiopental, an anesthetic period of time, i.e., a period of loss ofrighting-reflex was measured as the anesthetic effect. As a test drug,1H-tetrazole-1-acetic acid 2-methyl-1,3,4-thiadiazol-5-ylthiol ester wasdissolved in dimethyl sulfoxide and the test drug thus prepared wasorally administered to the animals at a rate of 0.05 ml/10 g weight onehour before the administration of sodium thiopental. The results areshown in Table below.

                  TABLE                                                           ______________________________________                                                          Amount of Period of                                                           Administra-                                                                             Time of                                                             tion      Anesthesia                                                          (P.O.)    (Average Value)                                   Compound          (mg/Kg)   (minutes)                                         ______________________________________                                        1H-Tetrazole-1-acetic acid                                                    2-methyl-1,3,4-thiadiazol-5-ylthiol                                           ester             400       33.8                                              1H-Tetrazole-1-acetic acid                                                    2-methyl-1,3,4-thiadiazol-5-ylthiol                                           ester             200       21.0                                              1H-Tetrazole-1-acetic acid                                                    2-methyl-1,3,4-thiadiazol-5-ylthiol                                           ester             100       10.3                                              Comparative Group  0         8.4                                              ______________________________________                                    

As is clear seen from Table as described above, the period of time ofanesthesia of 1H-tetrazole-1-acetic acid2-methyl-1,3,4-thiadiazol-5-ylthiol ester used in an amount of 400 mg/Kgis 4.02 times greater than that of the comparative group. Thus, theprolongation effect on the period of time of anesthesia according to thecompounds of Formula (I) of this invention is remarkable.

Also, 1H-tetrazole-1-acetic acid 2-methyl-1,3,4-thiadiazol-5-ylthiolester of this invention had a minimum inhibitory concentration of 50μg/mg to Corynebacterium diphtheriae P.W. 8 as the antibacterialactivity.

Furthermore, the 1,3,4-thiadiazole-5-thiol esters of Formula (I) of thisinvention are useful as acylating agents for amines and hydrazines,particularly as active esters of preparing cephalosporin compounds.

The 1,3,4-thiadiazole-5-thiol esters of Formula (I) of this inventioncan be prepared by reacting an 1,3,4-thiadiazole-5-thiol of the formula,##STR7## wherein R is a hydrogen atom or a methyl group, or itsderivative with 1H-tetrazole-1-acetic acid or its derivative.

The derivatives of the 1,3,4-thiadiazole-5-thiols which can be employedin this invention include the salts of an alkali metal such as sodiumand potassium; the reaction products of a trialkylaluminum such astrimethylaluminum and triethylaluminum; the silyl derivatives such asthe trimethylsilyl derivative and the triethylsilyl derivative; and thetrifluoroacetates. The 1,3,4-thiadiazole-5-thiols also exist in the formof the 1,3,4-thiadiazole-5-thiones or as a mixture with the1,3,4-thiadiazole-5-thiones, and are equivalent to the1,3,4-thiadiazole-5-thiones or the mixture which are accordinglyincluded, as equivalents, in the 1,3,4-thiadiazole-5-thiols of thisinvention.

The derivatives of the carboxylic group in the 1H-tetrazole-1acetic acidwhich can be employed in this invention include the acid halides, theacid anhydride, the mixed acid anhydrides, the acid amides, the esters,the acid azides and the nitrile.

Specific examples of suitable derivatives include the acid chloride; themixed acid anhydrides of a dialkylphosphoric acid such asdimethylphosphoric acid and diethylphosphoric acid, phenylphosphoricacid, diphenylphosphoric acid, dibenzylphosphoric acid, a halogenatedphosphoric acid such as chlorophosphoric acid and bromophosphoric acid,a dialkylphosphorous acid such as dimethylphosphorous acid anddiethylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuricacid, an alkylcarbonic acid such as methylcarbonic acid andethylcarbonic acid, an aliphatic carboxylic acid such as pivalic acid,pentanoic acid, isopentanoic acid, 2-ethylbutanoic acid, trichloroaceticacid and trifluoroacetic acid, an aromatic carboxylic acid such asbenzoic acid or the symmetric acid of the 1H-tetrazole-1-acetic acid;the acid amides of imidazole, an 4-substituted imidazole such as4-methylimidazole and 4-ethylimidazole, dimethylpyrazole, triazole,tetrazole, ammonia, methylamine, dimethylamine; the esters such asmethyl ester, ethyl ester, cyanomethyl ester, methoxymethyl ester, vinylester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester,trichlorophenyl ester, pentachlorophenyl ester, methanesulfonylphenylester, phenylazophenyl ester, phenyl ester, phenylthioester,p-nitrophenylthioester, 2,4-dinitrophenylthioester, p-cresylthioester,carboxymethylthioester, pyranyl ester, pyridyl ester,8-quinolylthioester, the ester of N,N-dimethylhydroxylamine,1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide or N-hydroxyphthalimide.

The amount of the 1,3,4-thiadiazole-5-thiol of Formula (III) or itsderivative which can be employed for the preparation of the1,3,4-thiadiazole-5-thiol esters of Formula (I) of this inventiontypically ranges from about 0.5 moles to about 2 moles, and preferablyfrom about 0.9 moles to about 1.2 moles, per mole of1H-tetrazole-1-acetic acid or its derivative.

When free 1H-tetrazole-1-acetic acid is used, it is necessary to employa dehydrating agent for condensation.

Appropriate dehydrating agents for condensation which can be employed inthis invention include N,N-dicyclohexylcarbodiimide,N,N'-diisopropylcarbodiimide,N-cyclohexyl-N'-morpholinoethylcarbodiimide,N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide,N,N'-diethyl-carbodiimide,N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide,N,N'-carbonyldi(2-methylimidazole),pentamethyleneketene-N-cyclohexylimine,diphenylketene-N-cyclohexylimine, an alkoxyacetylene such asmethoxyacetylene and ethoxyacetylene, an 1-alkoxy-1-chloroethylene suchas 1-methoxy-1-chloroethylene and 1-ethoxy-1-chloroethylene, a trialkylphosphite such as trimethyl phosphite and triethyl phosphite, ethylpolyphosphates, isopropyl polyphosphate, phosphorus oxychloride, thionylchloride, oxalyl chloride, triphenylphosphine,2-ethyl-7-hydroxybenzisoxazolium salt,2-ethyl-5-m-sulfophenylisoxazolium hydroxide inner salt,(chloromethylene)dimethylammonium chloride, SO₃-hexamethylphosphoramide, SO₃ -N,N-dimethylformamide, sulfonates,trifluoroacetic anhydride, diphenylphosphoric acid azide,diphenylphosphoric acid cyanide and any mixtures thereof.

The amount of the dehydrating agent for condensation is typically about0.5 mole to about 20 moles, and preferably about 1 mole to about 10moles, per mole of free 1H-tetrazole-1-acetic acid.

The reaction temperature which can be employed in the preparation of the1,3,4-thiadiazole-5-thiol esters of Formula (I) may be varied within awide range of temperatures. In general, the reaction temperature isabout -50° C. to about 100° C., and preferably -20° C. to about 50° C.

The reaction of this invention can be conducted, in general, atatmospheric pressure, but it is noted that the pressure employed is notlimited thereto. Generally the reaction is conducted in an atmosphere ofair. However, it may also be conducted in an atmosphere of an inert gassuch as nitrogen, argon and helium.

This reaction are generally conducted in a reaction medium. Any reactionmedium which is inactive to the reactants and can dissolve or suspendthe reactants can be employed in this invention.

Specific examples of suitable reaction media include dioxane, ethylacetate, methylene chloride, chloroform, hexane, trifluoroaceticanhydride and aqueous solutions of sodium hydroxide or potassiumhydroxide.

The amount of 1H-tetrazole-1-acetic acid or its derivative which can beemployed is typically about 1 g to about 50 g, and preferably about 5 got about 20 g, per 100 ml of the reaction medium.

After the reaction is substantially completed, the desired compounds ofFormula (I) can be recovered from the reaction mixture and purified bythe conventional techniques. For example, the reaction medium isevaporated from the reaction mixture and the crude product thus obtainedis washed, dried or recrystallized.

The cephalosporin compounds of Formula (II) of this invention can beprepared by reacting 7-aminocephalosporanic acid or its derivative withthe 1,3,4-thiadiazole-5-thiol ester of Formula (I).

According to the present process for the preparation of thecephalosporin compounds of Formula (II), the acylation of the 7-positionin the 7-aminocephalosporanic acid or its derivative and thesubstitution of the 3-position in the 7-aminocephalosporanic acid or itsderivative proceed selectively in one step to give the desired compoundsof Formula (II). Thus, the reaction operation is simple and the recoveryof the desired compounds of Formula (II) can be simplified. As a result,the desired compounds of Formula (II) having high purity can be obtainedat high yields.

Suitable examples of the derivatives of 7-aminocephalosporanic acidwhich can be employed in this invention include the salts of alkalimetals such as sodium and potassium; the salts of alkaline earth metalssuch as calcium and magnesium; the salts of nitrogen-containing organicbases such as trimethylamine, triethylamine, pyridine,N-methylpiperidine, N-methylmorpholine; and the esters which can beeasily released by catalytic reduction or chemical reduction or underother mild conditions, such as the toluenesulfonylethyl ester, benzylester, p-nitrobenzyl ester, phenacyl ester, diphenylmethyl ester, tritylester, t-butyl ester, an alkyloxymethyl ester such as methoxymethylester and ethoxymethyl ester, phenyloxymethyl ester, benzoyloxymethylester, acetyloxymethyl ester, 3,5-di(t-butyl)-4-hydroxybenzyl ester, andβ,β,β-trichloroethyl ester.

The amount of the 1,3,4-thiadiazole-5-thiol ester of Formula (I) whichcan be employed in the preparation of the cephalosporin compounds ofFormula (II) is typically about 0.5 mole to about 2.0 moles, andpreferably about 0.9 mole to about 1.2 moles, per mole of7-aminocephalosporanic acid or its derivative.

The preparation of the cephalosporin compounds of Formula (II) isgenerally conducted in a reaction medium. Any reaction medium which isinactive to the reactants can be employed in this invention.

Specific examples of suitable reaction media used include water,acetone, dioxane, acetonitrile, toluene, chloroform, methylene chloride,ethylene chloride, tetrahydrofuran, ethyl acetate, formic acid,pyridine, trifluoroacetic acid, N,N-dimethylformamide, methanol,ethanol, methoxy ethanol, diethyl ether, isopropyl ether,N,N-dimethylacetamide, dimethyl sulfoxide and any mixtures of water withthe above described organic reaction media.

The amount of 7-aminocephalosporanic acid or its derivative which can beemployed is typically about 1 g to about 50 g and preferably about 5 gto about 20 g per 100 ml of the reaction medium.

It is preferred that the reaction between 7-aminocephalosporanic acid orits derivative and the 1,3,4-thiadiazole-5-thiol ester of Formula (I) isconducted at a pH ranging from about 1 to about 9. A more preferred pHis about 3 to about 8.

The temperature of the above described reaction which can be employed inthis invention is about -50° C. to about 100° C., and preferably about0° C. to about 80° C. In general, the above described reaction iscarried out at atmospheric pressure, but it is noted that the pressureemployed is not limited thereto. The above described reaction may becarried out in an atmosphere of air, and preferably in an atmosphere ofan inert gas such as nitrogen, argon and helium.

The above described reaction is continued until the desired compound ofFormula (II) is produced in a most appropriate amount. The period oftime of the above described reaction typically ranges from about 10minutes to several tens of hours, and preferably from about 0.5 hour toabout 5 hours.

Further, in order to promote the above described reaction of thisinvention there can be employed a base including an alkali metalhydrogencarbonate such as sodium hydrogencarbonate and potassiumhydrogencarbonate, a trialkylamine such as trimethylamine andtriethylamine, pyridine; an inorganic acid salt such as a chloride,bromide, iodide, thiocyanate or nitrate of lithium, sodium, potassium orammonium; a metal compound such as cupric chloride, cupric bromide,cupric fluoride, cupric nitrate, cuprous nitrate, cupric sulfate,cuprous sulfate, cupric borate, copper metaborate, cupric phosphate,cupric cyanide, cuprous cyanide, cupric formate, cuprous formate, cupricacetate, cuprous acetate, copper propionate, copper citrate, cuprictartarate, cuprous tartarate, cupric benzoate, cuprous benzoate, cupricsalicylate, cuprous salicylate, ferric chloride, ferrous chloride; aLewis acid such as titanium tetrachloride, titanium tetrabromide,zirconium tetrachloride, silicon tetrachloride, tin tetrachloride,antimony trichloride, antimony pentachloride, bismuth trichloride,aluminum trichloride, aluminum tribromide, zinc dichloride, borontrifluoride, boron trichloride, boron tribromide; a quaternary ammoniumsalt such as tetramethylammonium chloride, tetraethylammonium bromide,dimethyldiphenylammonium chloride, triethylbenzylammonium bromide; and atetraalkylphosphonium halide such as tetramethylphosphonium chloride,tetraethylphosphonium bromide, and tetraphenylphosphonium iodide.

The amount of these compounds which can be employed to promote theabove-described reaction typically ranges from about 0.1 mole to about10 moles, and preferably from about 1 mole to about 5 moles, per mole of7-aminocephalosporanic acid or its derivative.

The reaction products are separated and collected by the conventionalmethods from the reaction mixture and the cephalosporin compounds ofFormula (II) of this invention can be isolated either as such or in theform of the salts or the esters. When the cephalosporin compounds ofFormula (II) are obtained in the form of the esters, the esters can beconverted into the cephalosporin compounds by catalytic reduction orchemical reduction or under other mild conditions.

The cephalosporin compounds of Formula (II) thus obtained can beconverted, by the conventional methods, into the salts of an alkalimetal such as sodium and potassium; the salt of ammonium; the salts ofan alkaline earth metal such as magnesium and calcium; and the salts ofdiphenylenediamine, dicyclohexylamine, dibenzylethylenediamine,triethylamine, tri-n-butylamine, triphenylamine, triallylamine,dibenzylamine, N,N-dibenzylaminoethanol, procaine, quinine,2-methylquinoline, 2-amino-5-nitrothiazole, 9-aminoacridine orguanylurea. These salts exhibit excellent features for preparingmedicaments, for example, from the view point of their water solubility.

The cephalosporin compounds of Formula (II) are useful as antimicrobialagents.

The following Examples are given to illustrate the present inventionmore specifically. However, it should be understood that the inventionis in no way limited by these Examples.

EXAMPLE 1

In 20 ml of trifluoroacetic anhydride were suspended 1.3 g of1H-tetrazole-1-acetic acid and stirred at 20° C. for 15 minutes. Thenthe trifluoroacetic anhydride and by-products were distilled off underreduced pressure, and to the residue was added a mixed solution of 1.3 gof 2-methyl-1,3,4-thiadiazole-5-thiol and 50 ml of ethyl acetate andstirred at 20° C. for 3 hours. The solution thus obtained was condensedto dryness to give 3.8 g of a solid, and the solid was dissolved in asmall amount of ethyl acetate, and then were added 20 ml of petroleumether thereto. The precipitate thus formed was collected by filtrationand dried to give 2.40 g of 1H-tetrazole-1-acetic acid2-methyl-1,3,4-thiadiazol-5-ylthiol ester the form of yellowish powderat a yield of 99%.

Elemental Analysis Values:

Calculated (%): C, 29.8; H, 2.5; N, 34.7; S, 26.4. Found (%): C, 29.9;H, 2.5; N, 34.5; S, 26.6.

Infrared Absorption Spectrum:

γ_(c=o) : 1762 cm⁻¹

NMR Spectrum (CDCl₃), δppm:

2.58 (s, 3H), 5.95 (s, 2H), 8.95 (s, 1H)

Ultraviolet Absorption Spectrum (in ethyl acetate):

λ_(max) =323 mμ

EXAMPLE 2

The same procedure as in Example 1 was repeated except that 1.2 g of1,3,4-thiadiazole-5-thiol were used instead of the 1.3 g of2-methyl-1,3,4-triadiazole-5-thiol. As a result, 2.2 g of1H-tetrazole1-acetic acid 1,3,4-thiadiazol-5-ylthiol ester were obtainedin the form of yellowish powder.

Elemental Analysis Values:

Calculated (%): C, 26.3; H, 1.8; N, 36.8; S, 28.1. Found (%): C, 26.5;H, 1.8; N, 36.5; S, 28.3.

Infrared Absorption Spectrum:

γ_(c=o) : 1765 cm⁻¹

EXAMPLE 3

In 100 ml of ethyl acetate were dissolved 1.3 g of2-methyl-1,3,4-thiazole-5-thiol and then 1.3 g of 1H-tetrazole-1-aceticacid with stirring, followed by a further addition of 2.06 g ofdicyclohexylcarbodiimide with stirring under cooling with ice. Themixture was stirred under cooling with ice for 4 hours and left to standat 0° C. for 20 hours. Then the precipitate of dicyclohexylurea wasseparated by filtration and the filtrate was washed twice with 30 ml ofsaturated sodium chloride aqueous solution and dehydrated with anhydrousmagnesium sulfate, and subsequently ethyl acetate was distilled at 25°C. under reduced pressure. The residue was dissolved in a small amountof ethyl acetate, and addition of 20 ml of petroleum ether theretoresulted in the formation of precipitates. The precipitates werecollected by filtration and dried to give 2.26 g of1H-tetrazole-1-acetic acid 2-methyl-1,3,4-thiadiazol-5-ylthiol ester ata yield of 93.4%. The analytical values of this product were the same asthose of Example 1.

EXAMPLE 4

In 20 ml of methylene chloride were dissolved 8 ml of trimethylaluminumsolution having 2.5 mol concentration in hexane and cooled to 0° C. Tothe solution were added 2.6 g of 2-methyl-1,3,4-thiadiazole-5-thiol at0° C. and the reaction was continued at 25° C. for 2.5 hours in anitrogen atmosphere with stirring. Then to the solution were added 1.4 gof 1H-tetrazole-1-acetic acid methyl ester and the reaction wascontinued at 25° C. for 6 hours with stirring. The reaction medium andunreacted substances were distilled from the reaction solution underreduced pressure and to the residue thus obtained were added 50 ml ofethyl acetate and insoluble materials were removed by filtration.Addition of 50 ml of petroleum ether to the filtrate resulted in theprecipitation of solids and the solids were collected by filtration anddried to give 2.31 g of 1H-tetrazole-1-acetic acid2-methyl-1,3,4-thiadiazol-5-ylthiol ester at a yield of 95%. Theanalytical values of the product were the same as those of Example 1.

EXAMPLE 5

The same procedure as in Example 4 was repeated except that 1.56 g of1H-tetrazole-1-acetic acid ethyl ester were used instead of the 1.4 g of1H-tetrazole-1-acetic acid methyl ester. As a result, 2.35 g of the same1H-tetrazole-1-acetic acid 2-methyl-1,3,4-thiazol-5-ylthiol ester as inExample 4 were obtained at a yield of 97%.

EXAMPLE 6

To a solution of 1.4 g of 7-aminocephalosporanic acid, 0.4 g of sodiumbicarbonate and 60 ml of water was added a solution of 1.2 g of the1H-tetrazole-1-acetic acid 2-methyl-1,3,4-thiadiazol-5-ylthiol ester asobtained in Example 1 and 10 ml of acetone with stirring. The mixedsolution thus obtained was further stirred at 60° C. for 4 hours in anitrogen atmosphere while adjusting the pH of the solution to 6.4 with a3% sodium bicarbonate aqueous solution. After completion of the reactionacetone was distilled from the reaction solution under reduced pressure,and the water layer was washed twice with 50 ml of ether. Then the pH ofthe water layer was adjusted to 3 with 3 N hydrochloric acid and thewater layer was extracted three times with 100 ml of ethyl acetate. Thenthe extract was dried over sodium sulfate, and the reaction medium wasdistilled to give 2.2 g of 7-(1H-tetrazol-5-ylacetamide)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid having a purity of 93.5% at a yield of 90.6%.

Ultraviolet Absorption Spectrum (in 3% sodium hydrogencarbonate aqueoussolution):

λ_(max) =272 mμ

In 100 ml of an aqueous solution containing 0.1 M sodium acetate and 0.2M sodium chloride were dissolved 1.44 g of the above describedcephalosporin compound and the pH of the solution was adjusted to 4.5with acetic acid. The solution thus prepared was flowed in a 150 mlcolumn packed with Amberlite XAD-2 (manufactured by Rohm & Haas Co.,Ltd.) to adsorb a desired product thereon. After washing with 3 l of a5% acetic acid aqueous solution and further with 750 ml of water, theproduct was dissolved in a 50% acetone aqueous solution and the solutioncontaining the desired product was freeze-dried to give 1.22 g ofpurified7-(1H-tetrazol-1-ylacetamide)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid having a purity of 99.1%.

Ultraviolet Absorption Spectrum (in 3% sodium bicarbonate aqueoussolution):

λ_(max) =272 mμ

Melting Point: 197° C.-200° C. (Decomp.)

NMR Spectrum (DMSO-d₆), δppm:

2.68 (s, 3H), 3.71 (dd, 2H), 4.39 (dd, 2H), 5.12 (d, 1H), 5.37 (s, 2H),5.73 (q, 1H), 9.33 (s, 1H), 9.49 (d, 2H).

In 2 ml of water were dissolved 0.92 g of the compound having a purityof 99.1% thus obtained and 0.17 g of sodium bicarbonate and the solutionwas filtered. To the filtrate were added 9 ml of 99% ethanol, and acrystal of sodium7-(1H-tetrazol-1-ylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylatewas collected by filtration.

Ultraviolet Absorption Spectrum (in 3% sodium bicarbonate aqueoussolution):

λ_(max) =272 mμ

NMR Spectrum (DMSO-d₆), δppm:

2.70 (s, 3H), 3.67 (dd, 2H), 4.57 (dd, 2H), 5.08 (d, 1H), 5.47 (s, 2H),5.65 (q, 1H), 9.50 (s, 1H), 9.72 (d, 2H)

EXAMPLE 7

The same procedure as in Example 6 was repeated except that 1.1 g of the1H-tetrazole-1-acetic acid 1,3,4-thiadiazol-5-ylthiol ester as obtainedin Example 2 were used instead of the 1.2 g of 1H-tetrazole-1-aceticacid 2-methyl-1,3,4-thiadiazol-5-ylthiol ester. As a result, 2.1 g of7-(1H-tetrazol-1-ylacetamido)-3-(1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid having a purity of 93.1% were obtained at a yield of 88.9%.

1 g of this compound was recrystallized from a 50% acetone aqueoussolution to give 0.55 g of a purified crystal having a melting point of155° C. (decomp.) and a purity of 98.5%.

Ultraviolet Absorption Spectrum (3% sodium hydrogencarbonate aqueoussolution): λ_(max) =273 mμ

EXAMPLE 8

To a solution of 1.4 g of 7-aminocephalosporanic acid, 30 ml ofN,N-dimethylformamide and 30 ml of water was added a solution of 1.2 gof 1H-tetrazole-1-acetic acid 2-methyl-1,3,4-thiadiazol-5-ylthiol ester,5 ml of N,N-dimethylformamide and 5 ml of water with stirring and themixed solution thus obtained was further stirred at 60° C. for 4 hour ina nitrogen atmosphere. After completion of the reaction theN,N-dimethylformamide and water were distilled from the reactionsolution, and to the residue were added 50 ml of water and 100 ml ofethyl acetate. The pH of the solution thus obtained was adjusted to 3with 3 N hydrochloric acid and then the solution was extracted withethyl acetate and further twice with 100 ml of ethyl acetate. Theextract was dried over sodium sulfate and the ethyl acetate wasdistilled to give 2.16 g of7-(1H-tetrazol-1-ylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid having a purity of 92.5% at a yield of 89.0%. The analytical valuesof this product was found to be in agreement with those of the productin Example 6.

While the invention has been described in detail and with reference tospecific embodiments thereof, it will be apparent to one skilled in theart that various changes and modifications can be made therein withoutdeparmtent from the spirit and scope thereof.

What is claimed is:
 1. An 1,3,4-thiadiazole-5-thiol ester of theformula, ##STR8## wherein R is a hydrogen atom or a methyl group.
 2. The1,3,4-thiadiazole-5-thiol ester of claim 1, wherein R is a hydrogenatom.
 3. The 1,3,4-thiadiazole-5-thiol ester of claim 1, wherein R is amethyl group.